What You Don't Know, You Can Sell

In places where access to antiretroviral therapy is widespread, people living with HIV are now dying from a common and curable coinfection: hepatitis C virus (HCV). HIV increases the risk for, and accelerates the rate of, liver disease from hepatitis C. Pegylated interferon and ribavirin, medications used to treat HCV, are less effective in people with HIV than in their HCV-monoinfected counterparts.

In 2011, the first hepatitis C protease inhibitors, Merck's boceprevir and Vertex's telaprevir, were approved based on trials in people with hepatitis C monoinfection. Both drugs are being studied in coinfected people, thanks to pressure from the international HIV/HCV community and encouragement from regulatory agencies.

Despite outrage from activists, Merck refused to study drug-drug interactions (DDIs) between boceprevir (Victrelis), their HCV protease inhibitor, and drugs commonly used to treat HIV, putting coinfected study volunteers at risk for drug-drug interactions in their own clinical trial.

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Drug-drug interactions can have serious consequences for HIV/HCV-coinfected people, who risk forfeiting current and future treatment options for HIV and possibly HCV as well. DDIs can lower drug concentrations to an ineffective level, leading to drug resistance, or increase drug concentrations, worsening side effects and leading to treatment discontinuation; they can even be life-threatening, as was the case with ribavirin and didanosine (DDI; Videx).

The boceprevir coinfection study opened in mid-2009, before Merck had performed drug-drug interaction studies with HIV protease inhibitors in healthy volunteers, a common step in drug development. Nonetheless, coinfected study volunteers were allowed to use them; in fact, by default, HIV protease inhibitors -- or Merck's own integrase inhibitor, raltegravir (Isentress) -- were the only HIV treatment options for study volunteers, since non-nucleoside reverse transcriptase inhibitors were not allowed. Activists kept asking Merck to perform DDIs throughout boceprevir's development, but Merck's attitude remained cavalier; they did not launch key drug-drug interaction studies until two years later, months after boceprevir was approved.

The results of DDI studies with three ritonavir-boosted HIV protease inhibitors, atazanavir/r (Reyataz), darunavir/r (Prezista), and lopinavir/r (Kaletra) in healthy volunteers (rather than the actual trial participants who were using boceprevir with HIV protease drugs for almost a year) were presented in March at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle. The news was not good. Combining boceprevir with these HIV protease inhibitors lowered concentrations of each HIV protease inhibitor, at both the highest and lowest (peak and trough) levels.

Boceprevir lowered the peak concentration of atazanavir/r by 25 percent, and the trough by 49 percent; darunavir/r peak decreased by 36 percent and trough by 59 percent; for lopinavir/r, coadministration with boceprevir dropped the peak concentration by 30 percent and trough by 43 percent. In turn, boceprevir levels dropped by 45 percent when coadministered with lopinavir/r and by 32 percent when administered with daruanvir/r; only atazanavir/r had no effect on the concentration of boceprevir.

Failure to characterize these drug-drug interactions put study participants -- and coinfected patients -- at an unacceptable level of risk, although clinical implications -- or real-life impact on HIV and hepatitis C treatment outcomes -- of these drug interactions are not clear. Nonetheless, the U.S. Food and Drug Administration warned that "drug interactions between the hepatitis C virus (HCV) protease inhibitor Victrelis (boceprevir) and certain ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitors (atazanavir, lopinavir, darunavir) can potentially reduce the effectiveness of these medicines when they are used together."

Regulators from the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) went a step further, recommending that "doctors treating patients co-infected with hepatitis C and HIV should be aware of the findings of the drug interaction study. They should not co-administer Victrelis with ritonavir-boosted darunavir or lopinavir in HIV and hepatitis C co-infected patients. Co-administration of Victrelis with ritonavir-boosted atazanavir may be considered on a case-by-case basis if deemed necessary in patients with suppressed HIV viral loads and with an HIV strain without any suspected resistance to the HIV regimen. Increased clinical and laboratory monitoring is warranted."

Vertex's rival protease inhibitor, telaprevir (Incivek) has outsold boceprevir: in the fourth quarter of 2011, telaprevir trounced boceprevir $456.8 million to $87 million. The opportunity to capture the coinfection market share may have motivated Merck's decision to delay drug-drug interaction studies. HCV is more likely to be diagnosed and treated in HIV-positive people than people with HCV alone, for several reasons. HIV treatment guidelines recommend HCV testing for all HIV-positive people; the infrastructure to deliver treatment is already in place; and hepatitis C is known to be more aggressive in people with HIV, so physicians and patients are more game to try for a cure.

After Vertex reported drug interactions between telaprevir and ritonavir boosted HIV protease inhibitors, boceprevir became a more attractive option for co-infected people. Merck's vice president of clinical research, Robin Issacs, alluded to off-label use in the company's February 8 press release. "Though VICTRELIS is not indicated for the treatment of chronic HCV in those who are also infected with HIV, we recognize that some physicians have prescribed or may be considering prescribing VICTRELIS for patients taking ritonavir-boosted HIV protease inhibitors. We felt it was important to share these data as part of our commitment to patient safety and transparency."

Where was Merck's commitment to safety during boceprevir's development? We can only hope that no patients have been harmed.

The boceprevir experience underscores the importance of timely DDI studies. There are other medications used by people with hepatitis C -- whether or not they are coinfected with HIV -- that warrant study, such as methadone, buprenorphine, and commonly prescribed psychiatric medications. Merck representatives have stated that the company will be more proactive with their promising second-generation hepatitis C protease inhibitor, MK-5172.

Activists have released a statement calling on regulatory agencies and pharmaceutical companies to study DDIs between experimental HCV drugs that are broken down by the body in a similar way with hormonal contraceptives, methadone, buprenorphine, lipid lowering agents, immunosuppressive drugs, herbal remedies, and commonly prescribed psychiatric medications in addition to HIV medications.

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